Ezio Tirelli

Amphetamine-Induced Conditioned Activity and Sensitization: The Role of Habituation to the Test Context and the Involvement of Pavlovian Processes

Behaviours associated with drug action can sometimes be elicited, in the absence of drug, by exposure to stimuli that were present during drug administration. Such a finding is usually interpreted as a conditioned drug effect. Often, however, the outcome could arise if drug administration in a particular environment retarded behavioural habituation to that environment. To test the habituation hypothesis of conditioned drug effects, mice received 10 daily injections of damphetamine (paired group) or saline (unpaired) in test boxes, and the converse injections in the colony room. Another group received saline in both environments. The apparatus and procedures yielded minimal habituation of behaviours (ambulation and rearing) over sessions. Only the paired group demonstrated behavioural sensitization, indicating environment-specific sensitization. The paired group also showed more ambulation and rearing than the others on the critical test of conditioning (saline injection in test box); moreover, their conditioning test scores were higher than those of the other groups on their first exposure to the test boxes, contradicting the habituation hypothesis. Further supporting the involvement of Pavlovian conditioning, levels of ambulation and rearing measured for 10min before each injection increased in the paired group, relative to the unpaired groups, over successive pairing sessions. Tests controlling for differential handling/injection experience produced results consistent with those previously obtained. Together, the findings are incompatible with the habituation hypothesis, and further support the role of Pavlovian conditioning.

Evidence for behavioral sensitization to cocaine in preweanling rat pups

Abstract While chronic intermittent administration of stimulants often induces behavioral sensitization in adulthood, stimulant sensitization has rarely been reported prior to weaning [around postnatal day (P) 21]. Consistent pairing of drug administration with the test context often facilitates sensitization in adults, yet young animals have been typically returned to the home cage immediately post-injection. To determine whether promoting context-dependent sensitization might facilitate expression of sensitization in preweanlings, Sprague-Dawley rats were injected daily from P14 to P20 with 0, 5, 15, or 30u2005mg/kg cocaine HC1 and placed for 30 min in either the experimental chamber or home cage. On P21 (test day), subjects were challenged with either 15u2005mg/kg cocaine or saline prior to placement in the experimental chamber. Significant sensitization of cocaine-induced stereotyped head movements was evident in animals given 15 or 30u2005mg/kg chronically in the experimental chamber, but not when these same doses were given in the home cage. Less consistent evidence for cocaine-induced sensitization was seen when examining locomotion, although trends for sensitization of this behavior were seen in animals chronically injected in either the test chamber or home cage. Thus, preweanlings can exhibit cocaine sensitization, particularly in terms of stereotypy, when tested shortly after the chronic exposure period, with expression of this sensitization being facilitated by pairing the chronic injections with the test context.

Neonatal and preweanling rats are able to express short-term behavioral sensitization to cocaine

The present study assessed the ability of suckling rats to express short-term behavioral sensitization to cocaine prior to weaning. Rat pups, aged either 3, 5, 10, 12, 17 or 19 days at the beginning of the experiment, were placed in a chamber after daily injection with cocaine (7.5 or 15 mg/kg. i.p.) for either 2 or 4 consecutive days, and were tested for behavioral responsiveness to cocaine in the same chamber 24 h later (at either 7, 14 or 21 days of age). Such a short post-treatment interval was adopted, along with a consistent pairing of the testing context with the drug effect and a sensitive technique of behavioral measurement (video recording), in order to maximize the possibility of detecting any cocaine sensitization. Locomotion was sensitized at all ages, after both regimens in 14-day-old pups, but solely after 2 injections in 21- and 4 injections in 7-day-old pups. Sensitization was also expressed via behaviors specific to each age. Four cocaine injections augmented cocaine-induced uncoordinated movements of head, paws and body (horizontal activity) in 7-day-old pups, and mouth movements in 14-day-old pups. In 21-day-old pups, sensitization was dose- and regimen-dependently expressed via adult-like stereotyped head movements. In neonatal 7-day-old pups, cocaine sensitization was also visible as reductions in immobility (both injection regimens). Contrary to previous studies, these results indicate that, given the use of an appropriate methodology, short-term sensitization to the motoric effects of cocaine can be expressed by suckling rats prior to weaning, even after relatively short regimens of daily injections.

Anticipatory responding, exclusive drug-context pairing and conditioned effects in sensitization to apomorphine-induced climbing in mice

1. The conditioning aspects of contextual sensitization were examined in the case of apomorphine-induced wall-climbing in mice, measuring onset latencies of the pharmacological response and controlling differential habituation to the test context during drug treatment. 2. Sensitization was generated in male out-bred mice which received intermittent i.p. injections of 0.4 mg/kg apomorphine over 9 daily sessions. On day 10, they were tested for contextual sensitization (all mice under apomorphine). On day 14, after 3 sessions of reinstatement, mice were tested for conditioned climbing (all mice under saline). 3. It was found that simultaneous exposure to both apomorphine and the test context facilitated the expression of a full-blown contextual sensitization (some non-contextual sensitization emerging too); importantly, sensitization was accompanied by a progressive shortening of the latencies to climb (before injections); conditioned climbing appeared only in mice pairing the drug with the test context, that response being absent in mice treated outside the context or never exposed to the context. 4. It is likely that contextual sensitization to apomorphine-induced climbing relies on Pavlovian conditioning processes rather than on habituation-related processes.

Verticalization of behavior elicited by dopaminergic mobilization is qualitatively different between C57BL/6J and DBA/2J mice

Behavioral effects of dopaminergic stimulation were evaluated in C57BL/6J mice and compared to the effects occurring in DBA/2J mice, an inbred strain with reduced densities of striatal dopamine receptors. Effects of apomorphine (0.5–64 mg/kg) alone and in combination with cocaine (30 mg/kg) were assessed using a time-sampling technique that classified climbing and leaning in separate categories. Locomotion was also assessed in a separate experiment. Climbing occurred in DBA/2J mice only at doses of apomorphine that were 16 times higher than the smallest effective dose in C57BL/6J mice; nevertheless, relative to baseline values, effects were fairly comparable. By contrast, whereas DBA/2J mice showed dose-dependent leaning under apomorphine, C57BL/6J mice exhibited little leaning even at doses not producing climbing, and only after the highest apomorphine dose was leaning significantly increased. Apomorphine was equipotent in inducing gnawing across strains, although somewhat less efficacious in DBA/2J mice. When given alone, cocaine produced significant climbing, but not leaning or gnawing, in either strain. Whereas cocaine potentiated apomorphine-induced climbing and gnawing in both strains, apomorphine-induced leaning was not consistently changed by cocaine in either strain. These effects were not indirectly due to hyperkinesia, since neither apomorphine alone nor apomorphine and cocaine in combination was stimulant; apomorphine alone reduced locomotor activity and attenuated cocaine-induced hyperkinesia. The present data do not support a unitary, purely quantitative, account of insensitivity to dopaminergic stimulation based upon low densities of striatal dopamine receptors in DBA/2J mice. Rather, this constellation of results is suggestive of qualitative interstrain dissimilarities in dopaminergic responsiveness that could reflect organizational differences in receptor populations.

Pharmacological characterization of the enhancement of apomorphine-induced gnawing in mice by cocaine

The present study was designed to provide additional information on the behavioral and pharmacological mechanisms associated with the augmentation of apomorphine-induced gnawing in C57BL/6J mice. (-)-Cocaine enhanced apomorphine-induced gnawing at doses devoid of effects on gnawing when given alone. The effect was stereoselective, with (+)-cocaine devoid of activity in this test. Peripheral synapses may also not be critical to the cocaine enhancement, as cocaine methiodide, a charged species, was also without effect. The local anesthetic actions of cocaine were evaluated with lidocaine, a local anesthetic without prominent dopaminergic actions. Like (-)-cocaine, lidocaine augmented the gnawing response to apomorphine without increasing climbing or gnawing when given alone. (+)-Amphetamine enhanced apomorphine-induced gnawing but only at a high dose that increased gnawing by itself. The selective dopamine uptake blocker. GBR 12909, augmented apomorphine-induced gnawing without increasing gnawing when given alone; however, unlike cocaine or lidocaine, GBR 12909 increased climbing at doses that augmented the gnawing response. These data indicate that the cocaine-augmented gnawing response to apomorphine does not appear to be the result of psychomotor stimulation per se. Rather, this effect may be due to blockade of dopamine uptake and/or the local anesthetic actions of cocaine.